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Misoprostol reduces time-to-delivery, oxytocin use and cesarean delivery, but increases abnormal uterine activity
OB S T E TR ICS
Misoprostol reduces time-to-delivery, oxytocin use and cesarean delivery, but increases abnormal uterine activity Sanchez-Ramos L, Kaunitz AM. Misoprostol for cervical ripening and labor induction: a systematic review of the literature. Clin Obstet Gynecol 2000; 43: 475d488.
OBJECTIVE To evaluate the efficacy and safety of misoprostol for cervical ripening and induction of labour at term. DESIGN Meta-analysis of randomized, controlled trials. DATA SOURCES Not described. STUDY SELECTION Randomized, controlled trials that compared misoprostol with placebo or other labour-inducing drugs for cervical ripening and induction of labour in viable pregnancies at term. Additional analyses were carried out on trials that compared different routes of misoprostol. DATA EXTRACTION Not described. MAIN OUTCOME MEASURES Pooled odds ratio (OR, 95% CI) for maternal and perinatal outcomes in the misoprostol groups, in relation to the comparison groups. MAIN RESULTS Forty-four trials, published between 1992 and 2000, were included in the meta-analysis. A total of 2791 women received misoprostol, with the sample size of the misoprostol groups ranging from 17 to 138. 5 studies were placebo-controlled, with the remainder involving comparison with an active agent, such as prostaglandin E2 (23 trials), oxytocin (12 trials), or Foley catheter or
Commentary This review gives an excellent and up-to-date account of published randomised trials of misoprostol for labour induction. This comprehensiveness is its strength. The statistical part (meta-analysis) is its weakness. ‘Lumping’ together all available data for vaginal and oral misoprostol, regardless of parity, membrane status, cervical favourability and dosage, produced some impressive numbers, but how trustworthy are they? My hospital has 6000 deliveries and more than 1000 inductions 8
Evidence-based Obstetrics and Gynecology (2001) 3, 8d9 doi:10.1054/ebog.2001.0213, available online at http://www.idealibrary.com on
extra-amniotic saline (three trials). Misoprostol was administered orally (50–200 lg) in four trials and vaginally (25–200 lg) in the remainder. The OR for vaginal delivery within 12 h (n"601 women in the misoprostol groups) was 2.1 (1.7–2.7) and within 24 hours (n"997) was 2.2 (1.8–2.6). The weighted mean difference in the interval to vaginal delivery was !3.2 hours (!3.9 to !2.5), in favour of misoprostol. The OR for oxytocin augmentation of labour (n"1803) was 0.18 (0.15–0.21). The OR for cesarean delivery (n"2791) was 0.88 (0.77–0.99). Misoprostol use increased the risks of tachysystole (OR 3.0, CI 2.4–3.7, n"1789) and hyperstimulation (OR 1.7, CI 1.3–2.4, n"1668), but there was no significant difference between groups in perinatal outcomes, such as Apgar score (7 at 5 min (OR 1.04, CI 0.61–1.8, n"1681) or neonatal intensive care admission (OR 0.99, CI 0.80–1.3, n"1371). Seven trials, involving a total of 1191 women, compared oral and vaginal administration of misoprostol. There was no significant difference between the two routes for any of the outcomes mentioned above, except for the rate of cesarean delivery, which was lower with oral misoprostol (OR 0.64, CI 0.48–0.86). CONCLUSION Misoprostol is more effective than other agents, including placebo, for the induction of labour at term and is associated with lower rates of cesarean delivery and oxytocin use. Although the risks of hyperstimulation and tachysystole are increased with misoprostol use, no apparent adverse perinatal effect is observed.
annually. If we switch to misoprostol, can we really expect to double the rate of vaginal delivery within 24 hours (OR 2.2, CI 1.8d2.6) and reduce the cesarean section rate (OR 0.88, CI 0.77d0.99)? Possibly. But should we use the same regimen for primiparas with intact membranes and unfavourable cervix and multiparas with ruptured membranes and favourable cervix? If we do, will the ‘lump sums’ still apply? More importantly, there is the safety issue. It is quite clear that lower doses of misoprostol ((50 lg) will be less effective, but they are also less likely to cause uterine hyperstimulation, ^ 2001 Harcourt Publishers Ltd
uterine rupture, and neonatal death. According to the authors, there was no significant difference between groups in perinatal outcomes. This is extremely good news. But never mind statistically significant differences. How many additional uterine ruptures and neonatal deaths would be clinically acceptable to women and clinicians these days? 1 per 100 inductions, 1 per 1000 inductions, 1 per 10,000 inductions, or none at all? Health professionals and the public need to engage in an open and honest debate on what are ‘acceptable’ risks of interventions during pregnancy in general and labour induction in particular. I suspect that there would be quite important differences from country to country, from one health care system to another.
^ 2001 Harcourt Publishers Ltd doi:10.1054/ebog.2001.0207, available online at http://www.idealibrary.com on
The mathematics are quite simple. If a consensus is reached that an increase in perinatal deaths from 1 per 1000 to 2 per 1000 is unacceptable, one needs to review the data on at least 50,000 women and, preferably, for each clinical scenario separately (e.g., primiparas versus multiparas, intact versus ruptured membranes, favourable versus unfavourable cervix). In other words, the ‘thumbs up’ decision for misoprostol is premature. The fact that we do not have comparable data for other prostaglandins (and oxytocin) is not an excuse that pregnant women will accept any more. Zarko Alfirevic, MD University of Liverpool, Liverpool, UK
Evidence-based Obstetrics and Gynecology (2001) 3, 8d9
9
Misoprostol reduces time-to-delivery, oxytocin use and cesarean delivery, but increases abnormal uterine activity Sanchez-Ramos L, Kaunitz AM. Misoprostol for cervical ripening and labor induction: a systematic review of the literature. Clin Obstet Gynecol 2000; 43: 475d488.
OBJECTIVE To evaluate the efficacy and safety of misoprostol for cervical ripening and induction of labour at term. DESIGN Meta-analysis of randomized, controlled trials. DATA SOURCES Not described. STUDY SELECTION Randomized, controlled trials that compared misoprostol with placebo or other labour-inducing drugs for cervical ripening and induction of labour in viable pregnancies at term. Additional analyses were carried out on trials that compared different routes of misoprostol. DATA EXTRACTION Not described. MAIN OUTCOME MEASURES Pooled odds ratio (OR, 95% CI) for maternal and perinatal outcomes in the misoprostol groups, in relation to the comparison groups. MAIN RESULTS Forty-four trials, published between 1992 and 2000, were included in the meta-analysis. A total of 2791 women received misoprostol, with the sample size of the misoprostol groups ranging from 17 to 138. 5 studies were placebo-controlled, with the remainder involving comparison with an active agent, such as prostaglandin E2 (23 trials), oxytocin (12 trials), or Foley catheter or
Commentary This review gives an excellent and up-to-date account of published randomised trials of misoprostol for labour induction. This comprehensiveness is its strength. The statistical part (meta-analysis) is its weakness. ‘Lumping’ together all available data for vaginal and oral misoprostol, regardless of parity, membrane status, cervical favourability and dosage, produced some impressive numbers, but how trustworthy are they? My hospital has 6000 deliveries and more than 1000 inductions 8
Evidence-based Obstetrics and Gynecology (2001) 3, 8d9 doi:10.1054/ebog.2001.0213, available online at http://www.idealibrary.com on
extra-amniotic saline (three trials). Misoprostol was administered orally (50–200 lg) in four trials and vaginally (25–200 lg) in the remainder. The OR for vaginal delivery within 12 h (n"601 women in the misoprostol groups) was 2.1 (1.7–2.7) and within 24 hours (n"997) was 2.2 (1.8–2.6). The weighted mean difference in the interval to vaginal delivery was !3.2 hours (!3.9 to !2.5), in favour of misoprostol. The OR for oxytocin augmentation of labour (n"1803) was 0.18 (0.15–0.21). The OR for cesarean delivery (n"2791) was 0.88 (0.77–0.99). Misoprostol use increased the risks of tachysystole (OR 3.0, CI 2.4–3.7, n"1789) and hyperstimulation (OR 1.7, CI 1.3–2.4, n"1668), but there was no significant difference between groups in perinatal outcomes, such as Apgar score (7 at 5 min (OR 1.04, CI 0.61–1.8, n"1681) or neonatal intensive care admission (OR 0.99, CI 0.80–1.3, n"1371). Seven trials, involving a total of 1191 women, compared oral and vaginal administration of misoprostol. There was no significant difference between the two routes for any of the outcomes mentioned above, except for the rate of cesarean delivery, which was lower with oral misoprostol (OR 0.64, CI 0.48–0.86). CONCLUSION Misoprostol is more effective than other agents, including placebo, for the induction of labour at term and is associated with lower rates of cesarean delivery and oxytocin use. Although the risks of hyperstimulation and tachysystole are increased with misoprostol use, no apparent adverse perinatal effect is observed.
annually. If we switch to misoprostol, can we really expect to double the rate of vaginal delivery within 24 hours (OR 2.2, CI 1.8d2.6) and reduce the cesarean section rate (OR 0.88, CI 0.77d0.99)? Possibly. But should we use the same regimen for primiparas with intact membranes and unfavourable cervix and multiparas with ruptured membranes and favourable cervix? If we do, will the ‘lump sums’ still apply? More importantly, there is the safety issue. It is quite clear that lower doses of misoprostol ((50 lg) will be less effective, but they are also less likely to cause uterine hyperstimulation, ^ 2001 Harcourt Publishers Ltd
uterine rupture, and neonatal death. According to the authors, there was no significant difference between groups in perinatal outcomes. This is extremely good news. But never mind statistically significant differences. How many additional uterine ruptures and neonatal deaths would be clinically acceptable to women and clinicians these days? 1 per 100 inductions, 1 per 1000 inductions, 1 per 10,000 inductions, or none at all? Health professionals and the public need to engage in an open and honest debate on what are ‘acceptable’ risks of interventions during pregnancy in general and labour induction in particular. I suspect that there would be quite important differences from country to country, from one health care system to another.
^ 2001 Harcourt Publishers Ltd doi:10.1054/ebog.2001.0207, available online at http://www.idealibrary.com on
The mathematics are quite simple. If a consensus is reached that an increase in perinatal deaths from 1 per 1000 to 2 per 1000 is unacceptable, one needs to review the data on at least 50,000 women and, preferably, for each clinical scenario separately (e.g., primiparas versus multiparas, intact versus ruptured membranes, favourable versus unfavourable cervix). In other words, the ‘thumbs up’ decision for misoprostol is premature. The fact that we do not have comparable data for other prostaglandins (and oxytocin) is not an excuse that pregnant women will accept any more. Zarko Alfirevic, MD University of Liverpool, Liverpool, UK
Evidence-based Obstetrics and Gynecology (2001) 3, 8d9
9